The olfactory bulb (OB) is one of the few structures in the adult forebrain in which there is a continuous supply of newborn neurons (Luskin, 1993; Alvarez-Buylla, et al., 2002). The neural progenitors, which originate from stem cells located in the subventricular zone (SVZ) of the lateral ventricles, follow an intricate path of migration before reaching their final position in the OB. First, they migrate tangentially, in chains, along the entire extent of the rostral migratory stream (RMS), and once in the bulb, turn to migrate radially out of the RMS into the outer layers, where they differentiate into inhibitory interneurons (Luskin, 1993; Alvarez-Buylla, et al., 2002).
Despite increasing knowledge on the origin, proliferation, and tangential migration of neuroblasts, the way by which they achieve their radial migration to functionally integrate into the bulbar circuitry remains elusive. Interestingly, radial glia, which are central for axonal guidance and radial migration during development, are no more present in the adult OB (Alvarez-Buylla, et al., 2002). This implies that neuroblasts arriving in the rostral extension of the RMS of adult forebrain follow unique migratory pathways, quite distinct from those observed at perinatal stages. Although a recent report has provided evidence that the OB-derived extracellular matrix (ECM) molecule reelin affects detachment of neuroblasts from chains, once they have reached the OB (Hack, et al., 2002), the identity of the cues halting tangential migration, initiating detachment of neuroblasts from the RMS and facilitating their radial migration have yet to be characterized. Furthermore, the impact of sensory experience in these processes needs to be examined.
The ability to generate neurons in the adult brain is relevant to the development of therapeutic strategies aimed at directing the migration and individualization of endogenous and/or grafted progenitor cells. Recently, it has been demonstrated that endogenous adult stem cells have the ability to regenerate functional neurons in non-neurogenic diseased areas (Magavi et al., 2000; Arvidsson, et al., 2002; Nakatomi, et al., 2002). Neuronal progenitors migrate to the damaged areas from the neurogenic source localized in the SVZ suggesting that not only increased proliferative activity following brain damage (Arvidsson, et al., 2002; Nakatomi, et al., 2002), but also changes either in the migratory capabilities of neuroblasts and/or in the microenvironment of the target tissues may help to recruit the newly generated neurons for repair. According to this invention, recruitment of neuronal progenitors in diseased areas of the nervous system can be considerably enhanced by application of TNR.
A better understanding of neural migration provides the basis for new treatments for neurological disease and damage, which are needed in the art. This invention aids in fulfilling this need.